Pre-RA: Can early diagnosis lead to prevention?

Abstract

Rheumatoid arthritis (RA) is currently diagnosed and treated once an individual displays the clinical findings of inflammatory arthritis (IA). However, growing evidence supports that there is a ‘pre-RA’ stage that can be identified through factors such as autoantibodies in absence of clinically-apparent IA. In particular, biomarkers including antibodies to citrullinated protein antigens (ACPA) demonstrate high risk for future IA/RA and multiple clinical trials have been developed to intervene in individuals in pre-RA to prevent or delay clinically-apparent disease. Herein, we will discuss in more depth what is currently known about the natural history of RA, and the emerging possibility that early ‘diagnosis’ of RA-related autoimmunity followed by an intervention can lead to the delay or prevention of the first onset of clinically-apparent RA.

Introduction

Rheumatoid arthritis (RA) is one of the most common chronic autoimmune inflammatory diseases, affecting approximately 1% of the population. RA’s primary manifestation is inflammatory arthritis (IA) and indeed arthritis forms the core of the established classification criteria for disease (1, 2). However, other organ systems such as the lungs and cardiovascular system can also be affected, likely due to direct autoimmune injury or due to effects of chronic inflammation. In addition, while existing therapies can improve outcomes in RA, the disease is associated with decreased well-being, and adverse personal and societal impact. Furthermore, therapies are costly in terms of direct medication costs as well as ancillary costs such as safety monitoring. As such, overall, RA leads to substantial morbidity, increased mortality and high financial costs.

In addition to the development of reasonably effective therapies for RA, one of the biggest advances in improving outcomes in RA has been the ability to identify and treat individuals with RA earlier in the disease course. Specifically, the institution of disease modifying anti-rheumatic therapy (DMARDs) within months of the symptomatic onset of RA and prior to substantial articular destruction has led to improved outcomes. Indeed, a goal of most published treatment guidelines in RA is the early identification of disease and institution of DMARD therapy (3, 4). This is largely because of a perceived ‘window of opportunity’ in RA that can be considered to include an ‘opportunity’ to control disease before it has led to substantial tissue damage; furthermore, there is a hope that early treatments can control and potentially even alter immunity before immune dysregulation may have evolved to a point where it is more difficult to improve (5, 6).

While earlier treatment is considered optimal in RA, current approaches to the diagnosis and initiation of treatment of RA still largely depend on the presence of clinically-apparent synovitis on physical examination. However, multiple studies now have established there is a ‘pre-RA’ period of development that can be characterized by detection of RA-related biomarkers, including autoantibodies, in the circulation years prior to the first appearance of a swollen joint (7). In particular, the fairly strong predictive value of certain biomarkers such as antibodies to citrullinated protein antibodies (ACPA) for future clinically-apparent IA and classifiable RA has supported the development and implementation of several clinical trials, some of which have been completed, for the prevention of the first clinically-apparent IA in RA.

In this chapter, we will discuss in more depth what is currently known about the natural history of RA, and the emerging possibility that early ‘diagnosis’ of RA-related autoimmunity followed by an intervention can lead to the prevention and/or delay of the first onset of clinically-apparent articular disease in RA.

Early treatment improves outcomes in RA: a window of opportunity

The typical approach to the management of RA is for an individual who develops articular symptoms of disease to proceed to evaluation by a health-care professional. In this patient-health-care provider interaction, IA is identified, additional tests are done to diagnose RA and treatment is initiated. Treatment is generally recommended to consist of disease modifying antirheumatic drug (DMARD) therapy that can include oral or injectable agents and balancing patient preferences and co-morbidities with optimizing disease control (3, 4).

Fortunately, modern therapies can improve disease activity and outcomes for many individuals with RA. However, while there are known cases of ‘palindromic’ RA where individuals may develop clinically-apparent IA that spontaneously goes into drug-free remission, for a substantial portion of individuals once the first clinically-apparent IA develops, their disease is ‘forever’ and requires life-long DMARD therapy. ‘Lifelong’ RA is a particularly likely outcome in individuals who exhibit seropositivity for RA-related autoantibodies including rheumatoid factor (RF) and antibodies to citrullinated protein antigens (ACPA)(8). In addition, for a substantial number of individuals with RA, while therapy improves disease activity, they do not attain full remission (9). Moreover, while drug-free remission is possible in RA, it is a rare occurrence (10-13).

There are many factors that play into why RA is largely a ‘forever’ disease after clinically-apparent IA develops. Most importantly, it is that breaks in tolerance have occurred and autoimmunity pathways have progressed to the point where they drive tissue injury and are unable to return to a quiescent state. In addition, even if immune-mediated tissue injury is controlled, once damage to a joint has occurred, ongoing mechanical effects can lead to increased joint injury. Importantly, it appears that these factors are potentially more amenable to modification and improvement if addressed soon after the onset of clinically-apparent IA. This latter point has underpinned a concept termed ‘the window of opportunity’ in the treatment of RA (14-16). More specifically, while not invariable, multiple studies have demonstrated that treating RA within 3 to 6 months from the onset of clinically-apparent IA can lead to improved outcomes and potentially increased rates of remission (17-20). Moreover, the importance of early diagnosis and treatment in improving outcomes in RA was a key part of the rationale for the development of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria which can classify an individual with RA earlier in the disease course than the 1987 criteria (1, 21). Indeed, while clinicians may treat for RA even without classification being met, multiple studies have demonstrated that the 2010 criteria are fulfilled earlier than the 1987 criteria (22).

Hypothesis: a ‘pre-RA’ state may be an earlier and better window of opportunity for management and even prevention of articular RA

RA is currently classified and treated based on the appearance of clinically-apparent IA; however, there are now a large number of studies demonstrating that at least for seropositive RA there is a ‘pre-RA’ period of disease development. Pre-RA can be defined in several ways, but a commonly accepted working definition is the presence of RA-related autoantibodies in the absence of and preceding the onset of clinically-apparent IA (23-25). In particular, the autoantibodies used to identify pre-RA have included RF and ACPA and there but there are also a growing number of other systems including antibodies to carbamylated proteins (anti-CarP), antibodies to peptidyl arginine deiminase (anti-PAD) and antibodies to malondialdehyde-acetaldehyde adducts (anti-MAA) (26-40).

The understanding of the immune dysregulation that occurs in pre-RA is rapidly evolving; however, based on current data, pre-RA is characterized by early reactivity to a limited number of self-antigens, and limited systemic inflammation. This is followed by evolution over time of expanding innate and adaptive responses and tissue injury that lead to clinical symptoms and ultimately clinically-apparent IA/RA develops. A model describing this process as a ‘stairstep’ approach to RA development is provided in Figure 1.

Figure 1. ‘Stairstep’ Model of Rheumatoid Arthritis (RA) Development.

In this model each step represents a ‘step’ in the development in RA. Abbreviations: RA=rheumatoid arthritis, ACPA=antibodies to citrullinated protein antigens; RF=rheumatoid factor; anti-CarP=antibodies to carbamylated proteins; anti-PAD=antibodies to peptidyl arginine deiminase

This ‘stairstep’ model is supported by published findings of increases over time in the numbers and type of ACPA (33, 35, 41, 42), as well as increases of other autoantibodies (e.g. anti-CarP, anti-PAD and anti-MAA antibodies) and systemic inflammation (e.g. cytokines) (36, 43, 44). Other processes that occur include changes in autoantibody glycosylation (45), and changes in cellular phenotypes including T cell subsets (46). It also appears that ACPA may precede RF and other autoantibodies (e.g. anti-CarP) (33, 34). A caveat is that these findings are variable across studies and do not hold in individuals with RA who may only be positive for RF, or be seronegative; however, they may indicate that in many individuals ACPA are indicative of the earliest breaks in tolerance, and that development of multiple types of autoantibodies participates in the transition to clinically-apparent disease. Of interest, while the hallmark of established RA is synovitis of diarthrodial joints, there is growing evidence that as individuals transition from pre-RA to clinically-apparent RA that the tenosynovium may be the ‘first’ articular structure involved with inflammation (47).

Importantly, while expansion of autoimmunity and inflammation characterize this period, it is not yet known what the key biologic pathways are that drive initial breaks in tolerance and early generation of autoimmunity and then a transition to a more pathogenic state and clinically-identifiable IA/RA. Moreover, many purported genetic, environmental and endogenous risk factors for RA have been identified only in individuals with clinically-apparent articular RA; therefore, the role of these factors in the initiation and propagation of autoimmunity and inflammation prior to clinically-apparent IA/RA is not well understood. It is also not clear if some factors identified in pre-RA are driving autoimmunity or are dysregulated as a part of autoimmunity. However, some risk factors that are associated with future risk for RA have been prospectively identified in Pre-RA (Table 1, and reviewed in (48, 49)). In particular, interactions between tobacco smoke and the shared epitope (SE) may play an important role in increasing the risk for a transition from autoantibody positivity to clinically-apparent IA/RA (42, 50, 51). In addition, many individuals with systemic elevations RA-related autoantibodies have no evidence of synovitis on physical exam, imaging, or synovial biopsy (52, 53). This strongly suggests that autoimmunity in these individuals is generated outside of the joints, with emerging evidence suggesting this site may be mucosal (e.g. lungs, periodontium, intestine) and related to the microbiome (reviewed in (54)). This stage of RA development may be non-articular and is an active area of investigation; importantly, it may prove ultimately to be useful to target these non-articular sites for RA prevention using approaches that are unique to these early, non-articular processes and different than articular disease (discussed further below).

Table 1.

Risk and protective factors for future RA development evaluated in prospective studies or cross-sectional studies

Genetic and familial risk factors

Shared epitope associated with higher risk for transition to clinically-apparent RA in ACPA positive individuals (55)

First-degree relative status increased risk of progression to clinically-apparent RA in arthralgia cohort (52)

Populations indigenous to the Americas who have ~5-7 fold increased risk for RA compared to non-indigenous populations; may have genetic and environmental influences (119)

Sex-related factors

Female sex given women have 2-3 fold higher risk for RA compared to men (48)

Longer duration of breast-feeding and higher parity are protective (120)

Oral contraceptive use associated with decreased autoantibody positivity in at-risk individuals without RA (first-degree relatives)(121)

Environmental (and potentially modifiable)(reviewed in (48) and (74))

Increased risk for RA

Tobacco exposure, especially long duration and high intensity smoking

Obesity

Inflammatory diet

Protective against RA

Moderate alcohol consumption

High fatty fish intake and intake of omega-3 fatty acids

Other

Lung disease (airways, parenchymal) present in RA-related autoantibody individuals and in some cases preceding articular RA (122)

Periodontal inflammation is present in RA-related autoantibody positive individuals, and increased in comparison to controls (117)

Increased levels of perceived stress as well as mental health issues including depression and anxiety are seen in pre-RA(95, 123)

Autonomic dysfunction has been identified in pre-RA(124)

Abbreviations: Pre-RA=pre-rheumatoid arthritis; ACPA=antibodies to citrullinated protein/peptide antigens

Beyond the insights that autoantibodies give into the pathogenesis of RA, the presence of autoantibodies can be predictive of future RA. In retrospective case-control studies of individuals known to later develop RA, the presence of RF and/or ACPA have demonstrated positive predictive values (PPVs) of >80% for future RA (30, 31). Due to the nature of case-control studies those PPV’s are likely overestimates of risk. However, multiple prospective studies have demonstrated that ~20 to 70% of individuals with RF and ACPA positivity progress to clinically-apparent IA after follow-up of 2-5 years. Furthermore, a larger percentage of individuals who have higher numbers of ‘risk factors’ appear to progress to RA, and in a shorter time period (Table 2) (52, 55). These ‘risk factors’ include ACPA positive (which has much higher stronger PPV for future RA than RF alone), higher levels of ACPA, positive for both RF and ACPA, presence of the shared epitope, higher level of symptoms of arthritis (e.g. joint pain, even in absence of clinically-apparent RA), and abnormalities on joint ultrasound.

Table 2.

Prediction of future inflammatory arthritis and rheumatoid arthritis in prospective studies of at-risk populations

Publication	Country of origin/population	Study type	Number of subjects and incident IA/RA	Key findings
del Puente et al 1988 (26)	USA, Akimel O’Odham (Pima) people	Prospective cohort study	2,712 subjects, 70 (~2.6%) with incident IA/RA after up to 19 years of follow-up.	The highest rate of development of RA (48 per 1000-person years) was in subjects with baseline RF titer of >1:256.
Silman et al 1992 (125)	United Kingdom	Prospective cohort study	370 unaffected first-degree relatives from families with RA; 14 with incident RA	Incident RA was highest in subjects with RF positivity.
Van de Stadt et al 2012 (126)	The Netherlands	Prospective study of individuals presenting to rheumatology clinics	347 subjects with RF and/or ACPA positivity but no IA at baseline; 131 with incident IA/RA after a median of 12 months.	A score was developed assigning 1 point for each of the following that were present: positive FDR status, no alcohol consumption (use of alcohol was protective), symptoms starting <12 months prior, intermittent symptoms, symptoms in upper and lower extremities, visual analog pain score of >=50 millimeters, more stiffness >=60 minutes, self-reported swelling in any joint; in addition, up to 4 points were assigned if both RF and ACPA were positive. In individuals with scores of >=7, 74% developed IA/RA within 3 years.
de Hair et al 2013 (76)	The Netherlands	Prospective study of ACPA and/or RF positive subjects	55 subjects, 15 (27%) with incident IA after a median of 13 months.	Non-smokers and those with normal body weight had the lowest rates of progression to IA/RA.
Ramos-Remus et al 2015 (39)	Mexico	Prospective study of unaffected FDRs of patients with RA	819 FDRS, 17 (2.1%) with incident IA/RA over 5 years.	ACPA positivity with or without concomitant RF positivity had PPV’s of 58-64% for development of RA during follow-up.
Rakieh et al 2015 (55)	United Kingdom	Prospective study of ACPA+ (CCP2) subjects with arthralgia referred to rheumatology clinics	100 ACPA+ individuals, 50 with incident IA/RA after a median of 7.9 months	A score was developed assigning 1 point for each of the following: tender joints, morning stiffness >30 minutes, presence of the shared epitope, high levels of RF and/or ACPA, and the presence of ultrasound power doppler findings in >=1 joint. In individuals with the highest scores (>=2), >41% developed IA/RA within 24 months, and individuals with scores of >=4, 68% developed IA within 24 months.
Burgers et al 2017 (127)	The Netherlands and Sweden	Prospective study of subjects with arthralgia	178 subjects with arthralgia meeting EULAR criteria for CSA at baseline, 44 (18%) developed with incident IA/RA after a median of 16 weeks.	Study to validate the EULAR definition for Clinical Suspect Arthralgia (128). The presence of 3 or more of the following factors was ~84% sensitive and had a PPV of ~30% for IA/RA within 2 years: duration of onset of symptoms <1 year, symptoms in MCP joints, morning stiffness >=60 minutes, more severe morning symptoms, having an FDR with RA, and on examination, difficulty making a fist and tenderness with an MCP squeeze. However, PPV for IA was much less if the criteria were applied by a non-rheumatologist practitioner (PPV ~3%).
Gan et al 2017 (40)	USA	Prospective cohort study	35 ACPA+ (CCP3) subjects with baseline IA identified through health-fair screenings; 14 with incident IA/RA after a mean of 2.6 years.	Progression to IA/RA was associated higher age, shared epitope positivity, and with lower blood levels of omega-3 fatty acids.

Abbreviations: RA=rheumatoid arthritis; IA=inflammatory arthritis; Ig=immunoglobulin; RF=rheumatoid factor; ACPA=antibody to citrullinated protein antigen; CCP=cyclic citrullinated peptide; USA=United States of America; MCP=metacarpal phalangeal joints; EULAR=European League Against Rheumatism

Due to the identification of pre-RA and also in large part to the strong predictive ability of ACPA for future RA, there has been a rethinking of a ‘window of opportunity’ in RA management (56). Specifically, it is now hoped that individuals can be identified in the pre-RA state (i.e. with some evidence of RA-related autoimmunity but no clinically-apparent IA), and then given an intervention to prevent or delay the onset of clinically-apparent IA (7). Notably, this approach has been supported in case series by the use of agents such as anti-malarials in individuals with palindromic rheumatism where some individuals have had delay or prevention of progression to persistent IA and classifiable RA (57-59). In addition, published studies of interventions in individuals with early clinically-apparent IA with agents such as steroids, methotrexate or abatacept, while not clearly successful to date in reversing autoimmunity or fully halting a progression to classifiable RA, have helped support that early treatment may lead to favorable changes in the disease process (60-64).

To date there have been three published clinical trials in which individuals with RA-related autoantibody positivity yet no clinically-apparent IA at baseline have been randomized to an immunologic intervention with the goal to delay or prevent the future onset of clinically-apparent IA (65-67). The details of these studies are provided in Table 3. In a study conducted in The Netherlands, 83 ACPA and/or RF positive individuals with arthralgia although without IA on physical examination were randomized (1:1) to receive two doses of dexamethasone 100 mg intramuscularly 6-weeks apart, or placebo (65). Rates of the development of IA were not different between arms (20% vs. 21%), although there was a decrease of autoantibody levels in individuals who received dexamethasone. In the PRAIRI trial (Prevention of clinically manifest rheumatoid arthritis by B-cell directed therapy in the earliest phase of the disease) study (68), 81 subjects with baseline ACPA and RF positivity and elevated C-reactive protein (>0.6 mg/L) were randomized (1:1) to receive 1000 mg rituximab for one dose, vs. placebo, and all subjects received methylprednisolone 100 mg intravenously. The rates of IA were not significantly different between arms (34% in treated vs. 40% in placebo); however, the onset of IA was delayed such that the time point at which 25% of subjects in the treated arm developed IA was ~12 months longer compared to placebo. In the STAPRA trial (Statins to Prevent Rheumatoid Arthritis), 62 individuals with ACPA levels 3 times the upper limit of normal or ACPA plus RF positivity were randomized (1:1) to receive atorvastatin 40 mg daily or placebo for 3 years (67). The rate of progression to IA was higher in the atorvastatin-treated subjects compared to placebo (29% vs. 19%) and the investigators concluded that atorvastatin was unlikely to prevent progression to RA although the study’s lower-than-expected enrollment (62 randomized compared to an original goal of 220) limited conclusions. In addition, the ARIAA study (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) was performed in 100 individuals with ACPA positivity and MRI signs of inflammation who received abatacept subcutaneously or placebo in a randomized, masked fashion, with outcomes including MRI changes of joint inflammation and the clinical appearance of IA (69). The knowledge of the results of this study are thus far limited because as of November 2021 it has only been published in abstract form; however, it appears that abatacept use significantly reduced MRI findings of inflammation as well as reduced progression to IA (70).

Table 3.

Published clinical trials of immunomodulatory therapy to prevent or delay the first clinically-apparent inflammatory arthritis in high-risk individuals

Study	Reference	Inclusion Criteria	Intervention	Primary Finding
Dutch Dexamethasone	Bos et al Ann Rheum Dis 2010(65)	RF and/or ACPA shared epitope positive arthralgia	Dexamethasone 100 mg x 2 doses vs. placebo	Overall, 17/83 (21%) participants developed IA over a median follow-up of 26 months. In the dexamethasone-treated group 9/42 (21%) developed IA demonstrating no difference in progression to IA over placebo-treated participants; dexamethasone was associated with decreased autoantibody levels.
PRAIRI	Gerlag et al Ann Rheum Dis 2019(66)	RF and ACPA Arthralgia	Rituximab 1000 mg x 1 dose (with concomitant corticosteroid) vs placebo for rituximab (but received corticosteroid)	Overall, 30/81 (37%) developed IA over a median follow-up 29 months. In the rituximab-treated arm 14/41 (34%) developed IA at a median of 16.5 months compared in the placebo group to 14/40 (40%) developing IA at a median 11.5 months. There was no significant difference in overall progression to IA; however, rituximab associated with delay of onset of IA ~12 months.
StapRA	Van Boheemen et al RMDOpen 2021(67)	RF and ACPA or high ACPA Arthralgia Calculated risk 55% of IA/RA within 3 years	Atorvastatin 40 mg daily x 3 years vs placebo	Overall, 15/62 (24%) participants developed IA during a median follow-up of 14 months. In the atorvastatin group, 9/31 (29%) developed IA at a median 9 months compared to the placebo group where 6/31 (19%) developed IA at a median of 4 months. There was no statistical difference in progression to IA.

There are several other prevention studies underway. StopRA (Strategy for the Prevention of the Clinically-Apparent Onset of RA) (71) in the United States is randomizing individuals with ACPA levels >=2x normal to receive hydroxychloroquine vs. placebo for 1 year; subjects are then followed for an additional 2 years to assess durability of response as well as to evaluate if treatment may result in a less-aggressive form of IA/RA. APPIPRA (Arthritis prevention in the preclinical phase of RA with abatacept) in the United Kingdom and Europe is randomizing individuals with ACPA levels >3x normal or ACPA plus RF, and inflammatory joint symptoms/arthralgia, to receive abatacept subcutaneously weekly for 1-year, versus placebo, with additional 1-year follow-up (72). Other studies that have been launched include one using glucocorticoids and methotrexate in individuals with arthralgia and no examination evidence of IA but who have ‘subclinical’ IA per magnetic resonance imaging (TREAT EARLIER [Treat early arthralgia to reverse or limit impending exacerbation to rheumatoid arthritis]) (73).

Challenges, opportunities and a vision to reach prevention in RA

An overview of a research agenda to move the field forward towards prevention in RA is provided in Table 4. In addition, the following sections describe in more detail specific aspects of prevention that will need to be addressed.

Table 4.

Research agenda to move forward rheumatoid arthritis prevention

Identification of effective targets for prevention, and assessing meaningful outcomes Accurate prediction Participation of at-risk individuals (including development of networks to facilitate identification and follow-up of at-risk individuals) Stakeholder involvement

Identification of effective targets for prevention, and assessing meaningful outcomes

The completed and ongoing clinical trials and observational studies of RA development discussed earlier will provide valuable knowledge as to the role each of the studied agents may play in prevention. Indeed, there are now published ‘points to consider’ that will help existing studies as well as future studies in ensuring that they are conducted in manner that will lead to optimal information being obtained (49). In addition, these studies of Pre-RA will also likely provide the field with new knowledge of this early period of RA development, perhaps identifying novel biologic pathways to target for prevention. This is important because current prevention trials are evaluating medications (corticosteroids, rituximab, hydroxychloroquine, abatacept and methotrexate) that are already approved and widely used for clinically-apparent RA. However, the biologic pathways that are critical to early breaks in tolerance and transition to clinically-apparent RA may differ from those that are present in established IA and as such novel interventions may been needed. In particular, if mucosal processes, including potential microbes, are indeed found to be critical to the initiation and propagation of autoimmunity in Pre-RA, these may be candidates for targeting (54). Furthermore, while lifestyle changes or supplements have not been strongly effective in treatment of established RA, given that the immune system may be more amenable to change in the pre-RA period, this may be an ideal time where changes such as weight loss, smoking cessation, improved diet or even addition of dietary factors such as omega-3 fatty acids, all of which may improve autoimmunity, could be implemented for prevention (40, 74-76).

Perhaps as important as selecting the right preventive intervention are the outcomes that are assessed. The published and ongoing clinical prevention trials are using as primary outcomes the development of clinically-apparent IA and classifiable RA as those are clinically-meaningful events that current drive the use of DMARD therapy in RA. However, going forward additional outcomes may be used to gauge ‘success’ in a prevention trial. While complete halt of the development of clinically-apparent IA is an outstanding goal for RA prevention, it may be that a delay in onset of IA still may be beneficial. In addition, while it would be admirable to have an intervention that could eliminate any evidence of autoimmunity (e.g. autoantibodies disappear), it may be that reasonable measures of success will be lowering if not elimination of autoantibodies, or prevention of the development of new autoantibodies (e.g. RF does not develop in an ACPA positive individual). Hopefully, the ongoing trials will provide insights into optimal outcomes.

Importantly, the length of the journey of an individual who first developing symptoms of IA to ultimately being diagnosis with RA and started on DMARD therapy depends on many factors. These factors include the biology of disease (e.g. how severe it is from its onset), personal awareness of symptoms and access to health care. In particular, access to health-care includes access to a health-care provider who is suspicious of RA, and also access to a health-care provider who is willing and able to prescribe DMARD therapy whether that be a rheumatologist or other type of provider (77). Given that there are fairly universal delays in diagnosing and treating clinically-apparent IA/RA which as discussed above are highly likely to adversely impact outcomes (77-81), even if complete prevention of future IA is still some time off, perhaps a benefit of preventive interventions may be to identify at-risk individuals early and facilitate early diagnosis and intervention. There is little formally published in this area although one abstract has suggested that ACPA positive individuals followed in a prospective study who converted to clinically-apparent IA had lower disease activity than individuals identified through normal clinical referrals (82). This will be an area of interest going forward.

Accurate prediction

In addition to effective interventions, a key part of prevention is accurate identification of individuals who are at sufficiently high-risk of developing a clinically-meaningful outcome that intervention is warranted. For RA, that can mean developing accurate models to predict which individuals will develop clinically-apparent disease and within a specific time frame. This could be seen as basically making a diagnosis of treatable RA-related autoimmunity earlier than could be done if clinically-apparent IA is used as the standard of diagnosis. The current prevention trials as well as ongoing natural history studies of RA will hopefully improve current predictions. This is perhaps most important for the design of clinical trials where pre-trial accurate estimates of the rates of transition to RA are critical for study design in terms of numbers of participants needed as well as to plan the duration of study to capture adequate numbers of outcomes.

There is growing evidence that imaging with modalities such as ultrasound (US) or magnetic resonance imaging (MRI) can identify IA or other inflammatory processes such as tenosynovitis before abnormalities are found on physical examination (83-86). In addition, some studies have demonstrated that US abnormalities can enhance the ability to identify autoantibody positive individuals who will go on to get clinically-apparent IA based on physical examination(55). Indeed, the ARIAA study mentioned above used MRI both to identify individuals with ‘subclinical’ joint inflammation, as well as an outcome measure for the efficacy of abatacept (69, 70). A similar approach may become more common in clinical trials as well as clinical care in individuals who exhibit RA-related autoimmunity yet do not have clear physical examination evidence of IA; indeed, these approaches may ultimately lead to determining that there is an additional imaging defined subclinical ‘articular’ stage of RA that requires treatment. However, there are still challenges to the use of imaging to ‘diagnose’ IA in the absence of clinical examination findings, or the use of imaging to predict future clinically-apparent RA; the challenges are due to high variability in user ability to identify findings as well as the growing knowledge that imaging may detect abnormalities that are not truly RA-related (87). While many clinicians are currently using imaging in early diagnosis of RA, further studies are needed to help define how these types of approaches can be used globally; in addition, while synovial biopsy is not yet widely done in pre-RA, findings from projects that are evaluating synovial biopsies in established RA may shed light on a possible role of synovial biopsy in pre-RA (88-91).

Importantly, while the appearance of clinically-apparent IA is an important finding to drive treatment in RA, there are many other symptoms associated with RA that are non-articular and indeed may be present prior to IA. These include fatigue, arthralgias in absence of clear tissue injury, as well as in rare cases conditions such as symptomatic lung disease or premature heart disease that may precede IA (92-94). In addition, there are a growing number of reports that mental health issues such as depression and anxiety may precede the onset of IA in RA (95). While mechanistic relationships between some of these clinical syndromes and RA-related autoimmunity need to be further understood, and there is a potential danger of overtreatment if immunomodulatory therapy is inappropriately used to treat fatigue that may not be autoimmune in nature, in the future, it may be that RA-related ‘autoimmune-opathy’ may be diagnosed and treated, even in absence of clinically-apparent IA.

Participation of at-risk individuals

A critical aspect of prevention is the participation of individuals in-whom prevention needs to be implemented. This is particularly challenging because individuals in the Pre-RA state may have little if any symptoms and therefore not seek out health-care or personal testing such as autoantibodies to determine their risk, although this may be different in individuals such as family members of patients with RA, who may be aware of RA and be concerned for their own personal risk or risk in their other family members.

To date, research studies have addressed finding at-risk individuals through a variety of ways including identification of RA-related autoantibody positive individuals without clinically-apparent IA in rheumatology clinics, with some groups in the United Kingdom and The Netherlands and elsewhere developing special clinics to facilitate the identification of at-risk individuals(52, 55, 96). In addition, other groups have performed studies of first-degree relatives or patients with RA (39, 97, 98), or broader general population screening through health-fairs or population-health activities (99-101).

Going forward, in order to drive research as well as ultimately implement prevention it will be critically important to develop well-crafted educational approaches that help individuals know what RA is, as well as interest them in assessing their own personal risk through blood testing or other modalities. Individuals’ preferences will also be an important consideration in choice of preventive interventions as well as other facets related to RA prevention – including nomenclature used to describe the various aspects of RA development (102, 103). This will need to take in account culture and other factors that surround evaluating risk for RA as well as potential preventive interventions (104). Two examples highlighting these latter points are the STAPRA trial where individuals at-risk for RA were reluctant to take the preventive intervention, even though statins are widely used (105); in addition, a EULAR study group found for individuals who are at-risk for RA that the term Pre-RA was not preferred because it may incorrectly apply a status to an individual who may never develop RA even if they have high-risk factors for future disease (25). Fortunately, some groups have implemented educational approaches for at-risk populations and these will provide a good set of first steps towards moving prevention forward (106, 107), although such studies could be expanded into larger networks of ‘at-risk’ individuals that can be utilized to facilitate research – similar to networks that have been created to facilitate prevention in other autoimmune diseases such as Type 1 Diabetes(108). Finally, an important part of gaining participation in prevention will be to make it ‘easy’ for individuals to be assessed for personal risk for RA; this could be through routine offering of testing for RA-related biomarkers similar to other testing such as for blood glucose and cholesterol, or through modalities such as home testing which is growing in ease and accuracy for a variety of tests and may be possible to determine RA risk.

Stakeholder involvement

As discussed above, perhaps the most important stakeholders who need to participate in development of preventive interventions for RA are individuals who are at high-risk for future RA. However, multiple other stakeholders will need to be involved as well including rheumatologists who will be the first to implement prevention given their familiarity with RA, a wide range of investigators including trialists, experts in outcome assessment, and basic scientists who can help identify meaningful targets for prevention. In addition, diagnostic industry, pharmacologic companies as well as payors (insurance agencies, governmental research funders as well as health-care payors) and regulatory agencies will need to be involved. Patient organizations may also be able to play key roles in prevention by promoting awareness and even helping to drive legislature that can ultimately support prevention. Importantly, because of the work done thus far in RA it will likely be one of the leaders in rheumatic disease prevention; however, lessons can be learned in terms of study design, nomenclature and infrastructure building to identify at-risk individuals from prevention in other autoimmune diseases such as Type 1 Diabetes where multiple trials have been performed to prevent or delay the clinical onset of disease (108-111).

Actions to be taken now in clinical care around prevention

Actionable RA prevention with pharmacologic intervention needs additional study and formal approvals of interventions; therefore, a primary goal should be to foster additional research in this area. However, given there are limited research studies available, there are some reasonable approaches that clinicians can currently take in the management of individuals who may be in a pre-RA state (See section on Practice Points). These include education about what RA is and what may be expected in terms of their personal risk for transitioning to clinically-apparent IA, and symptoms and signs to watch for in case IA develops. The optimal timing of clinical follow-up of these individuals has yet to be determined, however a reasonable approach may be to see these individuals in-person annually and additionally with any new changes in symptoms for a joint evaluation by a trained examiner and a refresher on education about RA. As for preventive interventions, pharmacologic interventions need to be determined; however, based on observational data and general health benefits it may be reasonable to recommend smoking cessation, exercise and reaching a healthy body-weight, and perhaps a diet that may be beneficial to inflammation such as a Mediterranean diet (74, 112-114). While there is emerging evidence that periodontal disease may be a risk factor for future RA, it is not yet clear whether addressing this needs to be a special preventive factor for RA beyond what is recommended for general dental health (74, 115-118).

Practice Points.

There are no currently approved therapies for the prevention of rheumatoid arthritis (RA). As such, it is not known what pharmacologic interventions would benefit individuals who are at high-risk for future RA; therefore, research should be promoted. However, if such individuals are encountered in clinical practice the following recommendations may be reasonable:

• Education about RA and signs and symptoms of development of RA

• Annual in-person follow-up with a rheumatologist for joint examination and education about RA, as well as with any new joint symptoms

• Counseling that based on current data, autoantibody positivity, especially positivity for antibodies to citrullinated protein antigens (ACPA) confer a risk of ~20-60% for onset of RA within 3-5 years

• Consideration for alterations of lifestyle factors that have general benefit and in observational studies have been associated with reduced risk for developing RA. These factors include:

  • Avoiding use of tobacco products
  • Maintenance of a health body weight
  • Regular aerobic exercise
  • Mediterranean diet
  • It is not known if addressing periodontal health will affect risk for RA

Summary

In conclusion, there have been great strides in the understanding of the natural history of RA development, and several clinical prevention trials have been completed or are underway. The near future should see published findings that may add preventive interventions to the management of RA.